1. Field of the Invention
The present invention relates to a method of reducing vascular permeability in tissue comprising inhibiting the activity of serine proteinase tissue-type plasminogen activator (tPA). This tPA activity which increases permeability of the tissue in a subject results in edema in the tissue is separate from tPA's thrombolytic activity. The present invention more specifically relates to administering an amount of a tPA inhibitor sufficient to reduce the vascular permeability increasing activity of tPA in a subject.
2. Description of the Related Art
Edema is an increase in the extravascular component of the extracellular fluid volume. It may be restricted to some organs, such as the brain (cerebral edema), the peritoneum (ascitis) or the pleaura (hydrothorax), or generalized (i.e., anasarca). Edema may result from a variety of pathophysiological events including damage or dysruption of the capillary endothelium with increases in its permeability and transfer of fluids to the extravascular compartment. This type of edema may be observed in patients with cerebral ischemia, head trauma, acute vascular occlusion (i.e., pulmonary embolism), and infection (i.e., sepsis), among others.
More specifically, in conditions in which cerebral edema is associated with pathological conditions, the opening of the blood brain barrier (BBB) results from pathologic increases in cerebrovascular permeability and is associated with the development of vasogenic edema and intracranial hypertension. BBB opening contributes to the morbidity and mortality of patients with many neurological disorders, including head trauma, subarachnoid hemorrhage. Additionally, it is one of the most common complications associated with ischemic stroke Garcia et al., Acta Neuropathol. (Berl) 43, 85-95 (1978); Baker et al., J. Neuropathol. Exp. Neurol. 30, 668-679 (1971).
Outside of the central nervous system (CNS), tPA is primarily a thrombolytic enzyme and its principal substrate is the zymogen plasminogen. Bugge et al., Cell 87, 709-719 (1996). However, within the CNS, tPA is thought to have a very different function, and its activity has been associated with events that require neuronal plasticity, such as long term potentiation and seizures. Tsirka et al., Nature 377, 340-344 (1995), Carroll et al., Development 120, 3173-3183 (1994), Qian et al., Nature 361, 453-457 (1993), Seeds et al., Science 270, 1992-1994 (1995), Yepes et al., J. Clin. Invest 109, 1571-1578 (2002). As a thrombolytic agent, tPA is the only FDA-approved thrombolytic medication for the treatment of patients with acute ischemic stroke (Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, N. Engl. J. Med. 333, 1581-1587 (1995)). In seeming contradiction, however, animal models of ischemic stroke have shown that both genetic deficiency of tPA (Wang et al., Nat. Med. 4, 228-231 (1998), Nagai et al., Circulation 99, 2440-2444 (1999)) and inhibition of tPA with its natural inhibitor, neuroserpin (Yepes et al., Blood 96, 569-576 (2000), Cinelli et al., Mol. Cell Neurosci. 18, 443-457 (2001)), are associated with a significant increase in neuronal survival and a decrease in stroke volume. Consistent with these latter studies, endogenous tPA activity within the CNS increases following middle cerebral artery occlusion (MCAO) (Wang et al., Nat. Med. 4, 228-231 (1998), Yepes et al., Blood 96, 569-576 (2000)), and thrombolytic treatment with tPA following embolic stroke is associated with evidence of increased vascular permeability (Zhang. et al. Circulation 106, 740-745 (2002), Aoki et al. Stroke 33, 2711-2717 (2002)). Thus, understanding the mechanisms leading to increased vascular permeability in tissue caused by increased levels of tPA in the affected tissue provides a platform for the development of effective therapeutic strategies aimed at the treatment of patients with pathological conditions associated with increased cerebrovascular permeability and cerebral edema, such as cerebral ischemia, head trauma, stroke and other neurological diseases as well as acute vascular occlusion, such as pulmonary embolism, and infection, such as sepsis.